RESUMO
In lung disease, persistence of KRT8-expressing aberrant basaloid cells in the alveolar epithelium is associated with impaired tissue regeneration and pathological tissue remodeling. We analyzed single cell RNA sequencing datasets of human interstitial lung disease and found the profibrotic Interleukin-11 (IL11) cytokine to be highly and specifically expressed in aberrant KRT8+ basaloid cells. IL11 is similarly expressed by KRT8+ alveolar epithelial cells lining fibrotic lesions in a mouse model of interstitial lung disease. Stimulation of alveolar epithelial cells with IL11 causes epithelial-to-mesenchymal transition and promotes a KRT8-high state, which stalls the beneficial differentiation of alveolar type 2 (AT2)-to-AT1 cells. Inhibition of IL11-signaling in AT2 cells in vivo prevents the accumulation of KRT8+ cells, enhances AT1 cell differentiation and blocks fibrogenesis, which is replicated by anti-IL11 therapy. These data show that IL11 inhibits reparative AT2-to-AT1 differentiation in the damaged lung to limit endogenous alveolar regeneration, resulting in fibrotic lung disease.
Assuntos
Células Epiteliais Alveolares , Diferenciação Celular , Interleucina-11 , Regeneração , Interleucina-11/metabolismo , Interleucina-11/genética , Animais , Regeneração/genética , Humanos , Camundongos , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Alvéolos Pulmonares/patologia , Alvéolos Pulmonares/metabolismo , Transição Epitelial-Mesenquimal/genética , Modelos Animais de Doenças , Doenças Pulmonares Intersticiais/patologia , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/metabolismo , Camundongos Endogâmicos C57BL , Masculino , Transdução de Sinais , FemininoRESUMO
Severe viral pneumonia can induce rapid expansion of KRT5+ basal-like cells in small airways and alveoli; this forms a scar-like structure that persists in the injured alveoli and impedes normal alveolar epithelium regeneration. In this study, we investigated the mechanism by which viral infection induced this remodeling response. Through comparing different lung-injury models, we demonstrated that infection induced strong IFN-γ signal-stimulated dysplastic KRT5+ cell formation. Inactivation of interferon receptor 1 (Ifngr1) reduced dysplastic cell formation, ameliorated lung fibrosis, and improved lung-function recovery. Mechanistically, IFN-γ regulated dysplastic cell formation via the focal adhesion kinase (FAK)/Yes-associated protein 1 (YAP) pathway. Inhibiting FAK/Src diminished IFN-γ-induced YAP nuclear translocation and dysplastic cell formation. Inhibiting YAP during viral infection prevented dysplastic cell formation, whereas inhibiting YAP in persistent KRT5+ cells led to their conversion into distal club cells. Importantly, human dysplastic cells exhibited elevated FAK and YAP activity, and IFN-γ treatment promoted the transformation of human alveolar progenitor cells into dysplastic cells. These findings uncover the role of infection-induced inflammatory response in alveolar remodeling and may provide potential therapeutic avenues for the treatment of alveolar remodeling in patients with severe viral pneumonia.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Quinase 1 de Adesão Focal , Interferon gama , Alvéolos Pulmonares , Proteínas de Sinalização YAP , Proteínas de Sinalização YAP/metabolismo , Animais , Camundongos , Humanos , Interferon gama/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Quinase 1 de Adesão Focal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Alvéolos Pulmonares/patologia , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/virologia , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Transdução de Sinais , Camundongos Knockout , Inflamação/patologia , Inflamação/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genéticaRESUMO
Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is an interstitial lung disease. In ACDMPV, respiratory impairment with severe pulmonary hypertension occurs from the early hours of life. Anomalies in the cardiovascular, gastrointestinal and genitourinary systems have been reported. However, little is known about upper airway abnormalities. We encountered a genetically diagnosed ACDMPV infant who presented with subglottic and bronchial stenosis. The prenatal diagnosis was hypoplastic left heart syndrome. Her respiratory condition worsened at 16 hours of life. We found subglottic stenosis when intubating. She died on day 7. Autopsy imaging with CT scan showed bilateral main bronchial stenosis. Chromosomal microarray revealed a 531 kb deletion in chromosome 16q24.1, including FOXF1.
Assuntos
Laringoestenose , Síndrome da Persistência do Padrão de Circulação Fetal , Alvéolos Pulmonares , Humanos , Feminino , Recém-Nascido , Síndrome da Persistência do Padrão de Circulação Fetal/complicações , Síndrome da Persistência do Padrão de Circulação Fetal/genética , Laringoestenose/etiologia , Evolução Fatal , Alvéolos Pulmonares/anormalidades , Alvéolos Pulmonares/patologia , Constrição Patológica , Veias Pulmonares/anormalidades , Veias Pulmonares/diagnóstico por imagem , Fatores de Transcrição ForkheadRESUMO
Current pharmacotherapy remains futile in acute alveolar inflammation induced by Gram-negative bacteria (GNB), eliciting consequent respiratory failure. The release of lipid polysaccharides after antibiotic treatment and subsequent progress of proinflammatory cascade highlights the necessity to apply effective inflammation management simultaneously. This work describes modular self-assembling peptides for rapid anti-inflammatory programming (SPRAY) to form nanoparticles targeting macrophage specifically, having anti-inflammation and bactericidal functions synchronously. SPRAY nanoparticles accelerate the self-delivery process in macrophages via lysosomal membrane permeabilization, maintaining anti-inflammatory programming in macrophages with efficacy close to T helper 2 cytokines. By pulmonary deposition, SPRAY nanoparticles effectively suppress inflammatory infiltration and promote alveoli regeneration in murine aseptic acute lung injury. Moreover, SPRAY nanoparticles efficiently eradicate multidrug-resistant GNB in alveoli by disrupting bacterial membrane. The universal molecular design of SPRAY nanoparticles provides a robust and clinically unseen local strategy in reverse acute inflammation featured by a high accumulation of proinflammatory cellularity and drug-resistant bacteria.
Assuntos
Infecções por Bactérias Gram-Negativas , Nanopartículas , Animais , Camundongos , Nanopartículas/química , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/administração & dosagem , Bactérias Gram-Negativas/efeitos dos fármacos , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia , Alvéolos Pulmonares/metabolismo , Administração por Inalação , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/administração & dosagem , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Inflamação/patologiaRESUMO
BACKGROUND: The alveolar epithelium is protected by a heparan sulfate-rich, glycosaminoglycan layer called the epithelial glycocalyx. It is cleaved in patients with acute respiratory distress syndrome (ARDS) and in murine models of influenza A (IAV) infection, shedding fragments into the airspace from the cell surface. Glycocalyx shedding results in increased permeability of the alveolar-capillary barrier, amplifying acute lung injury. The mechanisms underlying alveolar epithelial glycocalyx shedding in IAV infection are unknown. We hypothesized that induction of host sheddases such as matrix metalloproteinases (MMPs) during IAV infection results in glycocalyx shedding and increased lung injury. MATERIALS AND METHODS: We measured glycocalyx shedding and lung injury during IAV infection with and without treatment with the pan-MMP inhibitor Ilomastat (ILO) and in an MMP-7 knock out (MMP-7KO) mouse. C57BL/6 or MMP-7KO male and female mice were given IAV A/PR/8/34 (H1N1) at 30,000 PFU/mouse or PBS intratracheally. For some experiments, C56BL/6 mice were infected in the presence of ILO (100mg/kg) or vehicle given daily by IP injection. Bronchoalveolar lavage (BAL) and lung tissue were collected on day 1, 3, and 7 for analysis of glycocalyx shedding (BAL Syndecan-1) and lung injury (histology, BAL protein, BAL cytokines, BAL immune cell infiltrates, BAL RAGE). Expression and localization of the sheddase MMP-7 and its inhibitor TIMP-1 was examined by RNAScope. For in vitro experiments, MLE-12 mouse lung epithelial cells were cultured and treated with active or heat-inactivated heparinase (2.5 U/mL) prior to infection with IAV (MOI 1) and viral load and MMP-7 and TIMP-1 expression analyzed. RESULTS: IAV infection caused shedding of the epithelial glycocalyx into the BAL. Inhibition of MMPs with ILO reduced glycocalyx shedding by 36% (p = 0.0051) and reduced lung epithelial injury by 40% (p = 0.0404). ILO also reduced viral load by 68% (p = 0.027), despite having no significant effect on lung cytokine production. Both MMP-7 and its inhibitor TIMP-1 were upregulated in IAV infected mice: MMP-7 colocalized with IAV, while TIMP-1 was limited to cells adjacent to infection. However, MMP-7KO mice had similar glycocalyx shedding, epithelial injury, and viral load compared to WT littermates, suggesting redundancy in MMP sheddase function in the lung. In vitro, heparinase treatment before infection led to a 52% increase in viral load (p = 0.0038) without altering MMP-7 or TIMP-1 protein levels. CONCLUSIONS: Glycocalyx shedding and MMPs play key roles in IAV-induced epithelial injury, with significant impact on IAV viral load. Further studies are needed to understand which specific MMPs regulate lung epithelial glycocalyx shedding.
Assuntos
Glicocálix , Metaloproteinase 7 da Matriz , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae , Animais , Glicocálix/metabolismo , Camundongos , Feminino , Masculino , Metaloproteinase 7 da Matriz/metabolismo , Metaloproteinase 7 da Matriz/genética , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/virologia , Infecções por Orthomyxoviridae/patologia , Vírus da Influenza A Subtipo H1N1/fisiologia , Camundongos Knockout , Alvéolos Pulmonares/virologia , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia , Ácidos Hidroxâmicos/farmacologia , Inibidores de Metaloproteinases de Matriz/farmacologia , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Metaloproteinases da Matriz/metabolismo , IndóisAssuntos
Anestésicos Inalatórios , Hemorragia , Alvéolos Pulmonares , Sevoflurano , Humanos , Sevoflurano/efeitos adversos , Sevoflurano/administração & dosagem , Anestésicos Inalatórios/efeitos adversos , Anestésicos Inalatórios/administração & dosagem , Hemorragia/induzido quimicamente , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia , Masculino , Pneumopatias/induzido quimicamente , FemininoRESUMO
The evolution of T cell molecular signatures in the distal lung of patients with severe pneumonia is understudied. Here, we analyzed T cell subsets in longitudinal bronchoalveolar lavage fluid samples from 273 patients with severe pneumonia, including unvaccinated patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or with respiratory failure not linked to pneumonia. In patients with SARS-CoV-2 pneumonia, activation of interferon signaling pathways, low activation of the NF-κB pathway and preferential targeting of spike and nucleocapsid proteins early after intubation were associated with favorable outcomes, whereas loss of interferon signaling, activation of NF-κB-driven programs and specificity for the ORF1ab complex late in disease were associated with mortality. These results suggest that in patients with severe SARS-CoV-2 pneumonia, alveolar T cell interferon responses targeting structural SARS-CoV-2 proteins characterize individuals who recover, whereas responses against nonstructural proteins and activation of NF-κB are associated with poor outcomes.
Assuntos
COVID-19 , NF-kappa B , SARS-CoV-2 , Humanos , COVID-19/imunologia , SARS-CoV-2/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Idoso , Líquido da Lavagem Broncoalveolar/imunologia , Adulto , Transdução de Sinais/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Interferons/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/imunologia , Alvéolos Pulmonares/imunologia , Alvéolos Pulmonares/patologiaRESUMO
A middle-aged man presented with inferior wall ST-elevation myocardial infarction and underwent primary percutaneous coronary intervention with tirofiban administered due to extensive thrombus. He developed sudden-onset dyspnoea, bilateral crepitations, haemoptysis, desaturation and hypotension an hour after starting tirofiban infusion. The tirofiban, antiplatelet medications and heparin were stopped immediately. Chest X-ray showed patchy opacities in the left upper, middle and lower zones. High-resolution CT showed confluent areas of consolidation with surrounding ground glass opacities and interlobular septal thickening (crazy pavement appearance) representing diffuse alveolar haemorrhage (DAH). He was managed with inotropes, non-invasive ventilation and intravenous furosemide. He was asymptomatic with complete resolution of lung opacities in chest X-ray done 2 months follow-up. DAH is a rare but potentially life-threatening complication which is often misidentified with other respiratory syndromes. Treatment includes stopping tirofiban and anticoagulant medication, blood transfusion, and institution of mechanical ventilation.
Assuntos
Hemorragia , Alvéolos Pulmonares , Tirofibana , Humanos , Masculino , Pessoa de Meia-Idade , Hemorragia/induzido quimicamente , Pneumopatias/induzido quimicamente , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/efeitos adversos , Alvéolos Pulmonares/patologia , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Tirofibana/administração & dosagem , Tirofibana/efeitos adversos , Tomografia Computadorizada por Raios XRESUMO
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic disease. Recent studies have highlighted the persistence of an intermediate state of alveolar stem cells in IPF lungs. In this study, we discovered a close correlation between the distribution pattern of intermediate alveolar stem cells and the progression of fibrotic changes. We showed that amphiregulin (AREG) expression is significantly elevated in intermediate alveolar stem cells of mouse fibrotic lungs and IPF patients. High levels of serum AREG correlate significantly with profound deteriorations in lung function in IPF patients. We demonstrated that AREG in alveolar stem cells is both required and sufficient for activating EGFR in fibroblasts, thereby driving lung fibrosis. Moreover, pharmacological inhibition of AREG using a neutralizing antibody effectively blocked the initiation and progression of lung fibrosis in mice. Our study underscores the therapeutic potential of anti-AREG antibodies in attenuating IPF progression, offering a promising strategy for treating fibrotic diseases.
Assuntos
Anfirregulina , Progressão da Doença , Fibrose Pulmonar Idiopática , Anfirregulina/metabolismo , Animais , Humanos , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco/metabolismo , Receptores ErbB/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Masculino , Alvéolos Pulmonares/patologia , Alvéolos Pulmonares/metabolismo , Anticorpos Neutralizantes/farmacologia , FemininoRESUMO
Type 2 alveolar epithelial (AT2) cells of the lung are fundamental in regulating alveolar inflammation in response to injury. Impaired mitochondrial long-chain fatty acid ß-oxidation (mtLCFAO) in AT2 cells is assumed to aggravate alveolar inflammation in acute lung injury (ALI), yet the importance of mtLCFAO to AT2 cell function needs to be defined. Here we show that expression of carnitine palmitoyltransferase 1a (CPT1a), a mtLCFAO rate limiting enzyme, in AT2 cells is significantly decreased in acute respiratory distress syndrome (ARDS). In mice, Cpt1a deletion in AT2 cells impairs mtLCFAO without reducing ATP production and alters surfactant phospholipid abundance in the alveoli. Impairing mtLCFAO in AT2 cells via deleting either Cpt1a or Acadl (acyl-CoA dehydrogenase long chain) restricts alveolar inflammation in ALI by hindering the production of the neutrophilic chemokine CXCL2 from AT2 cells. This study thus highlights mtLCFAO as immunometabolism to injury in AT2 cells and suggests impaired mtLCFAO in AT2 cells as an anti-inflammatory response in ARDS.
Assuntos
Lesão Pulmonar Aguda , Células Epiteliais Alveolares , Carnitina O-Palmitoiltransferase , Ácidos Graxos , Mitocôndrias , Oxirredução , Síndrome do Desconforto Respiratório , Animais , Carnitina O-Palmitoiltransferase/metabolismo , Carnitina O-Palmitoiltransferase/genética , Mitocôndrias/metabolismo , Células Epiteliais Alveolares/metabolismo , Ácidos Graxos/metabolismo , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/genética , Camundongos , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/patologia , Síndrome do Desconforto Respiratório/genética , Masculino , Humanos , Quimiocina CXCL2/metabolismo , Quimiocina CXCL2/genética , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Neutrófilos/metabolismo , Camundongos Knockout , Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Acil-CoA Desidrogenase de Cadeia Longa/genética , Inflamação/metabolismo , Inflamação/patologia , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia , Alvéolos Pulmonares/imunologia , Trifosfato de Adenosina/metabolismo , Pneumonia/metabolismo , Pneumonia/imunologia , Pneumonia/patologia , Pneumonia/genéticaRESUMO
INTRODUCTION: Diffuse alveolar hemorrhage (DAH) is a rare complication with high mortality in patients with systemic lupus erythematosus (SLE). Early diagnosis and treatment are essential to improve patient prognosis. To determine the characteristics of patients with DAH and their mortality in a Spanish cohort of patients with SLE. METHODS: Patients from the RELESSER (Spanish Society of Rheumatology Lupus Register) who had had at least one confirmed episode of DAH were included. Epidemiological, clinical, and laboratory characteristics were analyzed. RESULTS: 4024 patients were included in the RELESSER register, 37 (0.9%), had at least one recorded episode of DAH. Only further data for 14 patients could be analyzed. In total, 92.9% were women, and for 4 (28.6%) DAH coincided with the debut of SLE. More than 80% of patients had renal involvement and thrombocytopenia. The most frequent manifestations were dyspnea (85.7%) and hypoxemia (100%), with the classic triad of hemoptysis, anemia and pulmonary infiltrates, appearing in 6 (46.2%) patients. The most frequently used treatments were glucocorticoids (85.7%) and cyclophosphamide (69.2%); plasmapheresis was utilized in 5 patients (35.7%) and 8, (57.1%) received intravenous immunoglobulins; 12 (85.7%) patients required admission to the ICU and 5 (35.7%) died. Tobacco use, history of lupus nephritis (LN), concomitant infection, and treatment with cyclophosphamide were more frequent in patients who died. CONCLUSIONS: DAH is rare in patients with SLE; in up to one-third of patients, it may appear at the onset of the disease. Some factors, such as smoking, a history of LN, treatment with cyclophosphamide, or concomitant infection, are more prevalent in patients with an unfavorable outcome.
Assuntos
Hemorragia , Pneumopatias , Lúpus Eritematoso Sistêmico , Sistema de Registros , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/epidemiologia , Feminino , Adulto , Espanha/epidemiologia , Masculino , Hemorragia/epidemiologia , Hemorragia/etiologia , Pneumopatias/epidemiologia , Pneumopatias/etiologia , Pneumopatias/terapia , Pessoa de Meia-Idade , Alvéolos Pulmonares/patologia , Glucocorticoides/uso terapêutico , Ciclofosfamida/uso terapêutico , Adulto Jovem , Imunossupressores/uso terapêutico , PlasmafereseRESUMO
RATIONALE: Cystic Fibrosis (CF) progresses through recurrent infection and inflammation, causing permanent lung function loss and airway remodeling. CT scans reveal abnormally low-density lung parenchyma in CF, but its microstructural nature remains insufficiently explored due to clinical CT limitations. To this end, diffusion-weighted 129Xe MRI is a non-invasive and validated measure of lung microstructure. In this work, we investigate microstructural changes in people with CF (pwCF) relative to age-matched, healthy subjects using comprehensive imaging and analysis involving pulmonary-function tests (PFTs), and 129Xe MRI. METHODS: 38 healthy subjects (age 6-40; 17.2 ± 9.5 years) and 39 pwCF (age 6-40; 15.6 ± 8.0 years) underwent 129Xe-diffusion MRI and PFTs. The distribution of diffusion measurements (i.e., apparent diffusion coefficients (ADC) and morphometric parameters) was assessed via linear binning (LB). The resulting volume percentages of bins were compared between controls and pwCF. Mean ADC and morphometric parameters were also correlated with PFTs. RESULTS: Mean whole-lung ADC correlated significantly with age (P < 0.001) for both controls and CF, and with PFTs (P < 0.05) specifically for pwCF. Although there was no significant difference in mean ADC between controls and pwCF (P = 0.334), age-adjusted LB indicated significant voxel-level diffusion (i.e., ADC and morphometric parameters) differences in pwCF compared to controls (P < 0.05). CONCLUSIONS: 129Xe diffusion MRI revealed microstructural abnormalities in CF lung disease. Smaller microstructural size may reflect compression from overall higher lung density due to interstitial inflammation, fibrosis, or other pathological changes. While elevated microstructural size may indicate emphysema-like remodeling due to chronic inflammation and infection.
Assuntos
Fibrose Cística , Imagem de Difusão por Ressonância Magnética , Testes de Função Respiratória , Isótopos de Xenônio , Humanos , Fibrose Cística/complicações , Fibrose Cística/diagnóstico por imagem , Fibrose Cística/fisiopatologia , Masculino , Feminino , Imagem de Difusão por Ressonância Magnética/métodos , Adolescente , Testes de Função Respiratória/métodos , Adulto , Criança , Alvéolos Pulmonares/diagnóstico por imagem , Alvéolos Pulmonares/patologiaRESUMO
Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an emerging adult-onset systemic autoinflammatory disorder affecting multiple organ systems. While lung involvement is common in this syndrome, literature regarding specific patterns is sparse. In this report, we present a case description of a patient with VEXAS syndrome who presented at the emergency department on two separate occasions with acute interstitial pneumonia (AIP) and diffuse alveolar hemorrhage (DAH). A literature review with a comparison of our observed findings to the general findings of VEXAS syndrome, AIP, and DAH is provided. This report underscores the rarity of specific pulmonary manifestations associated with VEXAS syndrome, contributing valuable insight to the limited literature available on this topic.
Assuntos
Hemorragia , Doenças Pulmonares Intersticiais , Alvéolos Pulmonares , Humanos , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/diagnóstico , Alvéolos Pulmonares/patologia , Masculino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Pneumopatias/patologia , Vacúolos/patologia , Pessoa de Meia-Idade , Síndrome , Enzimas Ativadoras de UbiquitinaRESUMO
Alveolar adenoma of the lung is a rare benign tumor first described in 1986. This article presents an observation of alveolar adenoma in a 72-year-old woman. Morphological and immunohistochemical methods of tumor diagnostics, issues of differential diagnosis are analyzed. The necessity of complex examination, including radiation methods, morphologic examination and immunohistochemical diagnostics to exclude other more dangerous diseases is shown.
Assuntos
Adenoma , Neoplasias Pulmonares , Humanos , Feminino , Idoso , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/diagnóstico , Adenoma/patologia , Adenoma/diagnóstico , Diagnóstico Diferencial , Alvéolos Pulmonares/patologiaRESUMO
Inflammation through activation of caspase-1, seems to play a role in pulmonary hypertension induced by alveolar hypoxia. Whether alveolar hypoxia induces caspase-1-mediated inflammation and influx of leukocytes in other organs than the lungs, is not known. Our aim was to explore sites of caspase-1-related inflammation in alveolar hypoxia. Wild type (WT) mice were exposed to environmental hypoxia or room-air, and organs were analyzed. Right heart catheterization was performed after 14 days of alveolar hypoxia in WT mice and mice transplanted with WT or caspase-1-/- bone marrow. Hypoxia induced leukocyte accumulation and increased caspase-1 protein in the lungs, not in other organs. WT mice transplanted with WT or caspase-1-/- bone marrow showed no difference in pulmonary leukocyte accumulation or development of pulmonary hypertension after alveolar hypoxia. Caspase-1 and IL-18 were detected in bronchial epithelium in WT mice, and hypoxia induced IL-18 secretion from bronchial epithelial cells. IL-18 stimulation generated IL-6 mRNA in monocytes. Phosphorylated STAT3 was increased in hypoxic lungs, not in other organs. Alveolar hypoxia induces caspase-1 activation and leukocyte accumulation specific to the lungs, not in other organs. Caspase-1 activation and IL-18 secretion from bronchial epithelial cells might initiate hypoxia-induced inflammation, leading to pulmonary hypertension.
Assuntos
Caspase 1 , Hipóxia , Inflamassomos , Interleucina-18 , Pulmão , Camundongos Endogâmicos C57BL , Animais , Masculino , Inflamassomos/metabolismo , Camundongos , Caspase 1/metabolismo , Caspase 1/genética , Pulmão/metabolismo , Pulmão/patologia , Interleucina-18/metabolismo , Interleucina-18/genética , Hipóxia/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Camundongos Knockout , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/patologiaRESUMO
Fibroblasts are present throughout the body and function to maintain tissue homeostasis. Recent studies have identified diverse fibroblast subsets in healthy and injured tissues1,2, but the origins and functional roles of injury-induced fibroblast lineages remain unclear. Here we show that lung-specialized alveolar fibroblasts take on multiple molecular states with distinct roles in facilitating responses to fibrotic lung injury. We generate a genetic tool that uniquely targets alveolar fibroblasts to demonstrate their role in providing niches for alveolar stem cells in homeostasis and show that loss of this niche leads to exaggerated responses to acute lung injury. Lineage tracing identifies alveolar fibroblasts as the dominant origin for multiple emergent fibroblast subsets sequentially driven by inflammatory and pro-fibrotic signals after injury. We identify similar, but not completely identical, fibroblast lineages in human pulmonary fibrosis. TGFß negatively regulates an inflammatory fibroblast subset that emerges early after injury and stimulates the differentiation into fibrotic fibroblasts to elicit intra-alveolar fibrosis. Blocking the induction of fibrotic fibroblasts in the alveolar fibroblast lineage abrogates fibrosis but exacerbates lung inflammation. These results demonstrate the multifaceted roles of the alveolar fibroblast lineage in maintaining normal alveolar homeostasis and orchestrating sequential responses to lung injury.
Assuntos
Lesão Pulmonar Aguda , Linhagem da Célula , Fibroblastos , Pneumonia , Alvéolos Pulmonares , Fibrose Pulmonar , Animais , Feminino , Humanos , Masculino , Camundongos , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/metabolismo , Diferenciação Celular , Fibroblastos/patologia , Fibroblastos/metabolismo , Homeostase , Pneumonia/patologia , Pneumonia/metabolismo , Alvéolos Pulmonares/patologia , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/metabolismo , Fibrose Pulmonar/patologia , Fibrose Pulmonar/metabolismo , Nicho de Células-Tronco , Células-Tronco/metabolismo , Células-Tronco/citologia , Células-Tronco/patologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
Excessive autophagy may lead to degradation and damage of alveolar epithelial cells after lung transplantation, eventually leading to alveolar epithelial cell loss, affecting the structural integrity and function of alveoli. Glutamine (Gln), a nutritional supplement, regulates autophagy through multiple signaling pathways. In this study, we explored the protective role of Gln on alveolar epithelial cells by inhibiting autophagy. In vivo, a rat orthotopic lung transplant model was carried out to evaluate the therapeutic effect of glutamine. Ischemia/reperfusion (I/R) induced alveolar collapse, edema, epithelial cell apoptosis, and inflammation, which led to a reduction of alveolar physiological function, such as an increase in peak airway pressure, and a decrease in lung compliance and oxygenation index. In comparison, Gln preserved alveolar structure and function by reducing alveolar apoptosis, inflammation, and edema. In vitro, a hypoxia/reoxygenation (H/R) cell model was performed to simulate IR injury on mouse lung epithelial (MLE) cells and human lung bronchus epithelial (Beas-2B) cells. H/R impaired the proliferation of epithelial cells and triggered cell apoptosis. In contrast, Gln normalized cell proliferation and suppressed I/R-induced cell apoptosis. The activation of mTOR and the downregulation of autophagy-related proteins (LC3, Atg5, Beclin1) were observed in Gln-treated lung tissues and alveolar epithelial cells. Both in vivo and in vitro, rapamycin, a classical mTOR inhibitor, reversed the beneficial effects of Gln on alveolar structure and function. Taken together, Glnpreserved alveolar structure and function after lung transplantation by inhibiting autophagy.
Assuntos
Autofagia , Glutamina , Transplante de Pulmão , Alvéolos Pulmonares , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Autofagia/efeitos dos fármacos , Animais , Glutamina/metabolismo , Glutamina/farmacologia , Masculino , Humanos , Camundongos , Ratos , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/patologiaRESUMO
Chronic interstitial lung diseases (ILDs) require frequent point-of-care monitoring. X-ray-based methods lack resolution and are ionizing. Chest computerized tomographic (CT) scans are expensive and provide more radiation. Conventional ultrasound can detect severe lung damage via vertical artifacts (B-lines). However, this information is not quantitative, and the appearance of B-lines is operator- and system-dependent. Here we demonstrate novel ultrasound-based biomarkers to assess severity of ILDs. Lung alveoli scatter ultrasound waves, leading to a complex acoustic signature, which is affected by changes in alveolar density due to ILDs. We exploit ultrasound scattering in the lung and combine quantitative ultrasound (QUS) parameters, to develop ultrasound-based biomarkers that significantly correlate (p = 1e-4 for edema and p = 3e-7 for fibrosis) to the severity of pulmonary fibrosis and edema in rodent lungs. These innovative QUS biomarkers will be very significant for monitoring severity of chronic ILDs and response to treatment, especially in this new era of miniaturized and highly portable ultrasound devices.
Assuntos
Doenças Pulmonares Intersticiais , Pulmão , Ultrassonografia , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/patologia , Ultrassonografia/métodos , Animais , Pulmão/diagnóstico por imagem , Pulmão/patologia , Humanos , Biomarcadores/análise , Masculino , Camundongos , Fibrose Pulmonar/diagnóstico por imagem , Fibrose Pulmonar/patologia , Ratos , Alvéolos Pulmonares/diagnóstico por imagem , Alvéolos Pulmonares/patologia , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: About 3% of patients with lupus develop severe diffuse alveolar hemorrhage (DAH) with pulmonary vasculitis. C57BL/6 (B6) mice with pristane-induced lupus also develop DAH, but BALB/c mice are resistant. DAH is independent of Toll-like receptor signaling and other inflammatory pathways. This study examined the role of the MEK1/2 pathway (MEK1/2-ERK1/2, JNK, p38). METHODS: B6 and BALB/c mice were treated with pristane with or without inhibitors of MEK1/2 (trametinib/GSK1120212 [GSK]), ERK1/2 (SCH772984 [SCH]), JNK, or p38. Effects on lung hemorrhage and hemostasis were determined. RESULTS: GSK and SCH abolished DAH, whereas JNK and p38 inhibitors were ineffective. Apoptotic cells were present in lung samples from pristane-treated mice but not in mice receiving pristane and GSK, and endothelial dysfunction was normalized. Expression of the ERK1/2-regulated transcription factor early growth response 1 increased in pristane-treated B6, but not BALB/c, mice and was normalized by GSK. Pristane also increased expression of the anticoagulant genes Tfpi and Thbd in B6 mice. The ratio of Tfpi to tissue factor (F3) to Tfpi increased in B6 (but not BALB/c) mice and was normalized by GSK. Circulating thrombomodulin protein levels increased in B6 mice and returned to normal after GSK treatment. Consistent with augmented endothelial anticoagulant activity, pristane treatment increased tail bleeding in B6 mice. CONCLUSION: Pristane treatment promotes lung endothelial injury and DAH in B6 mice by activating the MEK1/2-ERK1/2 pathway and impairing hemostasis. The hereditary factors determining susceptibility to lung injury and bleeding in pristane-induced lupus are relevant to the pathophysiology of life-threatening DAH in systemic lupus erythematosus and may help to optimize therapy.
Assuntos
Hemorragia , Hemostasia , Lúpus Eritematoso Sistêmico , MAP Quinase Quinase 2 , Sistema de Sinalização das MAP Quinases , Animais , Feminino , Camundongos , Modelos Animais de Doenças , Pulmão/patologia , Pneumopatias/etiologia , Lúpus Eritematoso Sistêmico/complicações , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 2/antagonistas & inibidores , MAP Quinase Quinase 2/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Alvéolos Pulmonares/patologia , Piridonas/farmacologia , Pirimidinonas/farmacologia , Terpenos/farmacologiaRESUMO
Alveolar, the smallest structural and functional units within the respiratory system, play a crucial role in maintaining lung function. Alveolar damage is a typical pathological hallmark of respiratory diseases. Nevertheless, there is currently no simple, rapid, economical, and unbiased method for quantifying alveolar size for entire lung tissue. Here, firstly, we conducted lung sample slicing based on the size, shape, and distribution of airway branches of different lobes. Next, we performed HE staining on different slices. Then, we provided an unbiased quantification of alveolar size using free software ImageJ. Through this protocol, we demonstrated that C57Bl/6 mice exhibit varying alveolar sizes among different lobes. Collectively, we provided a simple and unbiased method for a more comprehensive quantification of alveolar size in mice, which holds promise for a broader range of respiratory research using mouse models.